Summary The overall goal of the proposed studies is to characterize the role of IRX4204, a second generation retinoid X receptor (RXR) agonist in activating nuclear receptor related-1 protein (Nurr1)-mediated neuroprotection and preventing ?-synuclein (?-syn) neurodegeneration. Specifically, we propose to conduct plasma pharmacokinetic and brain accumulation studies to establish drug dose, plasma concentration, brain concentration and Nurr1 downstream gene response relationship to better understand the efficacy, safety and mechanisms of action of IRX4204 for translational Parkinson's disease (PD) drug discovery. Moreover, as a proof of concept, we will test whether oral administration of IRX4204 can protect against ?-syn-mediated neurodegeneration in a rat model of PD.